Compounds having particular antifolate activities are known as chemotherapeutic agents. U.S. Pat. No. 5,344,932 describes a method for manufacturing particularly substituted pyrrolo[2,3-d]pyrimidine-based antifolate derivatives including pemetrexed, and European Patent Application Publication No. 0434426 discloses a series of 4-hydroxypyrrolo[2,3-d]pyrimidine-L-glutamic acid derivatives.
Pemetrexed, a 5-substituted pyrrolo[2,3-d]pyrimidine, is a multi-targeted antifolate exhibiting anticancer activity by suppressing the activities of metabolites involved in folate metabolism in various kinds of cancer including non-small cell lung cancer.
Pemetrexed has been known to target thymidylate synthase (TS) and dihydrofolate reductase (DHFR) when it is activated into polyglutamate derivatives by folylpolyglutamate synthetase (FPGS), after it is introduced into the cells via reduced folate carrier (RFC), which is a major intracellular transport channel for folates.
Pemetrexed, already developed in the brand name of ALIMTA™, is currently available on the market as an agent for treating malignant pleural mesothelioma and non-small cell lung cancer (Physicians' Desk Reference, 60th ed., pp. 1722-1728 (2006)). ALIMTA™ is currently sold in the market in the form of a lyophilized formulation (100 mg or 500 mg), which requires reconstitution prior to administration, i.e., when it is administered to a patient, it should be reconstituted with 0.9% sodium chloride solution and finally diluted with 0.9% sodium chloride solution (final concentration of 0.25 mg/mL).
The manufacturing process for formulations of the type of lyophilized powder is complex and its processing requires high cost. Additionally, there is a risk of microbial contamination during the reconstitution of lyophilized formulations, and pharmacists, doctors, nurses, etc. who are involved in preparing medicine are highly likely to be exposed to cell-destroying materials. Accordingly, in the case of a cytotoxic anticancer agent such as pemetrexed, it is necessary to develop a ready-to-use liquid formulation which can be stored for a long period of time, rather than a lyophilized formulation.
In many cases, the problem in liquid formulations lies in their instability during storage. Due to the instability, many injectable formulations are used in the form of a lyophilized formulation, which is dissolved immediately before injection. In the case of pemetrexed or a pharmaceutically acceptable salt thereof, which has been provided in the form of a lyophilized formulation, the manufacture in the form of an aqueous solution may lead to an increase in the amount of unknown impurities and thus a long-term storage at room temperature may not be possible. For stability reasons, they have still been used in the form of lyophilized formulations in clinical studies.
Several formulations have been suggested to overcome the problems described above. For example, U.S. Pat. No. 6,686,365 (Korean Patent Application Publication No. 2002-0081293) discloses a stable liquid pemetrexed formulation, which is a liquid pemetrexed formulation containing a therapeutically effective amount of pemetrexed, an effective amount of an antioxidant, and a pharmaceutically acceptable excipient, wherein the antioxidant is selected from the group consisting of monothioglycerol, L-cysteine, and thioglycolic acid.
However, the above patent reportedly has a problem in that precipitation occurs during the progress of long-term storage stability test at 25° C., and it thus cannot secure stability for the desired period (International Patent Publication No. WO 2012/015810). Until today, no liquid pemetrexed formulation having long-term storage stability has been experimentally or commercially successful. The present inventors prepared a liquid formulation comprising pemetrexed using L-cysteine, the antioxidant described above, performed its stability test, and found that problems, such as changes in characteristics such as discoloration, etc., increase in impurities, decrease in pH, etc., occurred from the second week under stress testing conditions. Additionally, the present inventors prepared liquid formulations comprising pemetrexed using more than sixty stabilizers including ascorbic acid, sodium thiosulfate, butylated hydroxyanisole, propyl gallate, EDTA, L-methionine, acetylcysteine, etc. However, all of these formulations did not have the appropriate stability.